During aging, the neuronal response to endogenous and exogenous environmental stress undergoes continuous modulation. The accumulation of protein fragments, such as amyloid beta-peptide (Abeta), within brain parenchyma and vasculature provides a modified context in which homeostatic and reparative processes must be operative. The central theme of our Program Project is that specific, cell-associated cofactors, RAGE (Receptor for AGEs) and ABAD (Abeta binding alcohol dehydrogenase) are critical for concentrating the effects of low levels of Abeta, relevant to early stages of pathogenicity in Alzheimer's disease (AD) and cerebrovascular amyloid angiopathy (CAA), on vulnerable cells. Yet, in distinct settings, these same cofactors appear to have a pivotal role in triggering neuroprotective pathways and in orchestrating reparative processes through a complex integration of host response mechanisms. Project 1 evaluates the role of RAGE in the central nervous system, (CNS) in the potentiation of Abeta-induced cell stress by cross-breeding transgenic (Tg) mice with targeted over-expression of RAGE in cortical neurons and/or microglia with mice over-expressing mutant betaAPP, the latter resulting in an Abeta-rich environment. Project 2 examines a contrasting a protective role of RAGE in the peripheral nervous system (PNS); transient expression of RAGE in injured peripheral nerve and infiltrating macrophages interacts with two other RAGE ligands, amphoterin and EN-RAGEs (Extracellular, Newly- identified RAGE binding proteins), both of which are also present at sites of injury. in the PNS, to enhance identified RAGE binding proteins), both of which are also present at sites of injury in the PNS, to enhance reparative mechanisms. Projects 3-4 extrapolate our concept of chronic cellular perturbation in AD to the enzyme ABAD, an intracellular target of Abeta mediating generation of reactive oxygen intermediates and aldehydes in an Abeta-rich environment using Tg (#3) and in vitro models (#4), as well as structural studies go to probe ABAD-Abeta complex (#4). Analysis of overlapping cellular effector mechanisms triggered by activation of RAGE and ABAD results in critical shared molecular tools and animals models, and provides the basis for synergy among the four projects. At the end of this PROGRAM PROJECT, we expect to have generated new and important information related to the involvement of RAGE and ABAD in neuronal perturbation and repair as a first step in evaluating their efficacy as future therapeutic targets in neurodegenerative disorders.